Chemotherapy

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by SynergyBlades (talk | contribs) at 17:59, 29 September 2007 (Undid revision 161085424 by 194.109.164.2 (talk)). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Chemotherapy is the use of chemical substances to treat disease. In its modern-day use, it refers primarily to cytotoxic drugs used to treat cancer.

In its non-oncological use, the term may also refer to antibiotics (antibacterial chemotherapy). In that sense, the first modern chemotherapeutic agent was Paul Ehrlich's arsphenamine, an arsenic compound discovered in 1909 and used to treat syphilis. This was later followed by sulfonamides discovered by Domagk and penicillin G discovered by Alexander Fleming.

Other uses of cytostatic chemotherapy agents (including the ones mentioned below) are the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis and the suppression of transplant rejections (see immunosuppression and DMARDs).

History

Main article: History of cancer chemotherapy

The first drug used for cancer chemotherapy was not originally intended for that purpose. Mustard gas was used as a chemical warfare agent during World War I and was studied further during World War II. During a military operation in World War II, a group of people were accidentally exposed to mustard gas and were later found to have very low white blood cell counts. It was reasoned that an agent that damaged the rapidly growing white blood cells might have a similar effect on cancer. Therefore, in the 1940s, several patients with advanced lymphomas (cancers of certain white blood cells) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable. That experience led researchers to look for other substances that might have similar effects against cancer. As a result, many other drugs have been developed to treat cancer, and drug development since then has exploded into a multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply.

Principles

Cancer is the uncontrolled growth of cells coupled with malignant behavior: invasion and metastasis. Cancer is thought to be caused by the interaction between genetic susceptibility and environmental toxins. Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body - in other words, the body attacks its own cells. In contrast, transplant rejection happens because a normal healthy human immune system can distinguish foreign tissues and attempts to destroy them. Also the reverse situation, called graft-versus-host disease, may take place.

Broadly, most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells they are termed cytotoxic. Some drugs cause cells to undergo apoptosis (so-called "programmed cell death").

Unfortunately, scientists have yet to identify specific features of malignant and immune cells that would make them uniquely targetable (barring some recent examples, such as the Philadelphia chromosome as targeted by imatinib). This means that other fast dividing cells such as those responsible for hair growth and for replacement of the intestinal epithelium (lining) are also often affected. However, some drugs have a better side-effect profile than others, enabling doctors to adjust treatment regimens to the advantage of patients in certain situations.

As chemotherapy affects cell division, tumours with high growth fractions (such as acute myelogenous leukemia and the aggressive lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time. Malignancies with slower growth rates, such as indolent lymphomas, tend to respond to chemotherapy much more modestly.

Drugs affect "younger" tumors (i.e. more differentiated) more effectively, because mechanisms regulating cell growth are usually still preserved. With succeeding generations of tumour cells, differentiation is typically lost, growth becomes less regulated, and tumours become less responsive to most chemotherapeutic agents. Near the center of some solid tumours, cell division has effectively ceased, making them insensitive to chemotherapy. Another problem with solid tumours is the fact that the chemotherapeutic agent often does not reach the core of the tumour. Solutions to this problem include radiation therapy (both brachytherapy and teletherapy) and surgery.

Over time, cancer cells become more resistant to chemotherapy treatments. Recently, scientists have identified small pumps on the surface of cancer cells that actively move chemotherapy from inside the cell to the outside. Research on p-glycoprotein and other such chemotherapy efflux pumps, is currently ongoing. Medications to inhibit the function of p-glycoprotein are undergoing testing as of June, 2007 to enhance the efficacy of chemotherapy.

Treatment schemes

There are a number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.

Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiation therapy or surgery. Most cancers are now treated in this way. Combination chemotherapy is a similar practice which involves treating a patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects. The biggest advantage is minimising the chances of resistance developing to any one agent.

In neoadjuvant chemotherapy (preoperative treatment) initial chemotherapy is aimed for shrinking the primary tumour, thereby rendering local therapy (surgery or radiotherapy) less destructive or more effective.

Adjuvant chemotherapy (postoperative treatment) can be used when there is little evidence of cancer present, but there is risk of recurrence. This can help reduce chances of resistance developing if the tumour does develop. It is also useful in killing any cancerous cells which have spread to other parts of the body. This is often effective as the newly growing tumours are fast-dividing, and therefore very susceptible.

Palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, a better toxicity profile is generally expected.

All chemotherapy regimens require that the patient be capable of undergoing the treatment. Performance status is often used as a measure to determine whether a patient can receive chemotherapy, or whether dose reduction is required.

Types

The majority of chemotherapeutic drugs can be divided in to: alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, monoclonal antibodies, and other antitumour agents. All of these drugs affect cell division or DNA synthesis and function in some way.

Some newer agents don't directly interfere with DNA. These include the new tyrosine kinase inhibitor imatinib mesylate (Gleevec® or Glivec®), which directly targets a molecular abnormality in certain types of cancer (chronic myelogenous leukemia, gastrointestinal stromal tumors).

In addition, some drugs may be used which modulate tumor cell behaviour without directly attacking those cells. Hormone treatments fall into this category of adjuvant therapies.

Where available, Anatomical Therapeutic Chemical Classification System codes are provided for the major categories.

Alkylating agents (L01A)

Main article: Alkylating antineoplastic agent

Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. Cisplatin and carboplatin, as well as oxaliplatin are alkylating agents.

Other agents are mechloethamine, cyclophosphamide, chlorambucil. They work by chemically modifying a cell's DNA.

Anti-metabolites (L01B)

Main article: antimetabolite

Anti-metabolites masquerade as purine ((azathioprine, mercaptopurine)) or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. They also affect RNA synthesis. Due to their efficiency, these drugs are the most widely used cytostatics.

Plant alkaloids and terpenoids (L01C)

These alkaloids are derived from plants and block cell division by preventing microtubule function. Microtubules are vital for cell division and without them it can not occur. The main examples are vinca alkaloids and taxanes.

Vinca alkaloids (L01CA)

Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phase of the cell cycle). They are derived from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). The vinca alkaloids include:

Podophyllotoxin (L01CB)

Podophyllotoxin is a plant-derived compound used to produce two other cytostatic drugs, etoposide and teniposide. They prevent the cell from entering the G1 phase (the start of DNA replication) and the replication of DNA (the S phase). The exact mechanism of its action still has to be elucidated.

The substance has been primarily obtained from the American Mayapple (Podophyllum peltatum). Recently it has been discovered that a rare Himalayan Mayapple (Podophyllum hexandrum) contains it in a much greater quantity, but as the plant is endangered, its supply is limited. Studies have been conducted to isolate the genes involved in the substance's production, so that it could be obtained recombinantively.

Taxanes (L01CD)

The prototype taxane is the natural product paclitaxel, originally known as Taxol and first derived from the bark of the Pacific Yew tree. Docetaxel is a semi-synthetic analogue of paclitaxel. Taxanes enhance stability of microtubules, preventing the separation of chromosomes during anaphase.

Topoisomerase inhibitors (L01CB and L01XX)

Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling.

Antitumour antibiotics (L01D)

See main article: antineoplastic

The most important immunosuppressant from this group is dactinomycin, which is used in kidney transplantations.

Monoclonal antibodies

Monoclonal antibodies work by targeting tumour specific antigens, thus enhancing the host's immune response to tumour cells to which the agent attaches itself. Examples are trastuzumab (Herceptin), cetuximab, and rituximab (Rituxan or Mabthera). Bevacizumab is a monoclonal antibody that does not directly attack tumor cells but instead blocks the formation of new tumor vessels.

Hormonal therapy

Several malignancies respond to hormonal therapy. Strictly speaking, this is not chemotherapy. Cancer arising from certain tissues, including the mammary and prostate glands, may be inhibited or stimulated by appropriate changes in hormone balance.

Some other tumours are also hormone dependent, although the specific mechanism is still unclear.

Dosage

Dosage of chemotherapy can be difficult: if the dose is too low, it will be ineffective against the tumor, while at excessive doses the toxicity (side-effects, neutropenia) will be intolerable to the patient. This has led to the formation of detailed "dosing schemes" in most hospitals, which give guidance on the correct dose and adjustment in case of toxicity. In immunotherapy, they are in principle used in smaller dosages than in the treatment of malignant diseases.

In most cases, the dose is adjusted for the patient's body surface area, a measure that correlates with blood volume. The BSA is usually calculated with a mathematical formula or a nomogram, using a patient's weight and height, rather than by direct measurement.

Delivery

Most chemotherapy is delivered intravenously, although there are a number of agents that can be administered orally (e.g. melphalan, busulfan, capecitabine). In some cases, isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumour sites without causing overwhelming systemic damage.

Depending on the patient, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an inpatient or outpatient basis. For continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access. Commonly used systems are the Hickman line, the Port-a-Cath or the PICC line. These have a lower infection risk, are much less prone to phlebitis or extravasation, and abolish the need for repeated insertion of peripheral cannulae.

Harmful and lethal toxicity from chemotherapy limits the dosage of chemotherapy that can be given. Some tumours can be destroyed by sufficiently high doses of chemotheraputic agents. Unfortunately, these high doses cannot be given because they would be fatal to the patient.

Newer and experimental approaches

Hematopoietic stem cell transplant approaches

Stem cell harvesting and autologous or allogeneic stem cell transplant has been used to allow for higher doses of chemotheraputic agents where dosages are primarily limited by hematopoietic damage. Years of research in treating solid tumors, particularly breast cancer, with hematopoeitic stem cell transplants, has yielded little proof of efficacy. Hematological malignancies such as myeloma, lymphoma, and leukemia remain the main indications for stem cell transplants.

Isolated infusion approaches

Isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumours. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumour sites without causing overwhelming systemic damage. (Unfortunately, while these approaches can be useful against solitary or limited metastases, they are - by definition - not systemic and therefore do not treat distributed metastases or micrometastases).

Specially targeted delivery mechanisms toward higher effective doses and reduced toxicity

Specially targeted delivery vehicles aim to increase effective levels of chemotherapy for tumour cells while reducing effective levels for other cells. This should result in an increased tumour kill and/or reduced toxicity.

Specially targeted delivery vehicles have a differentially higher affinity for tumour cells by interacting with tumour specific or tumour associated antigens.

In addition to their targeting component, they also carry a payload - whether this is a traditional chemotheraputic agent, or a radioisotope or an immune stimulating factor. Specially targeted delivery vehicles vary in their stability, selectivity and choice of target, but in essence they all aim to increase the maximum effective dose that can be delivered to the tumour cells. Reduced systemic toxicity means that they can also be used in sicker patients, and that they can carry new chemotheraputic agents that would have been far too toxic to deliver via traditional systemic approaches.

Nanoparticles

Nanoparticles have emerged as a useful vehicle for poorly-soluble agents such as paclitaxel. Abraxane, also known as nab-paclitaxel, was approved by the US FDA in January 2005 for the treatment of refractory breast cancer, and allows reduced use of the Cremophor vehicle usually found in paclitaxel.

Minicells

Bacterially-derived minicells (MacDiarmid J.A. et al. (2007). "Bacterially Derived 400 nm Particles for Encapsulation and Cancer Cell Targeting of Chemotherapeutics" Cancer Cell 11, 431–445, May 2007) are a new approach to selectively delivering chemotherapy to target tumour cells, awaiting research trials in human subjects.

Minicells (aka. EDVs) are surrounded by a rigid and stable biological membrane. Therefore, unlike liposomes, the EDVs do not fall apart or leak and release the payload to non-target cells. This results in minimal to no toxicity from it's chemotheraputic payload.

Minicells can be readily packaged with a wide range of different anti-cancer drugs including : Doxorubicin, Paclitaxel, Vinblastine, 5-Fluorouracil, Irinotecan, Cisplatin, recently developed drugs like mitotic inhibitors etc.

Minicells are specifically targeted to the desired cancer cells in-vivo by virtue of a bispecific antibody where one arm carries anti-minicell specificity and the other arm has specificity to a relevant tumor cell-surface receptor (e.g. EGFR, HER2/neu etc). The minicells are then selectively absorbed into the cancer cells by endocytosis.

Targeted minicells (aka. EDVs) have been shown to be very stable and therapeutically effective in-vivo (tumor xenograft models and endogenous tumor dog model). Most recently, studies in 60 rhesus monkeys have demonstrated the safety of high dose minicells.

Most importantly, minicells offer the potential to safely deliver extremely high effective dosages of chemotherapy selectively to cancer cells. Even highly chemotherapy-resistant tumor cells like melanoma can be destroyed by sufficiently high dose chemotherapy (as studies in isolated limb perfusion have demonstrated). The problem is that such high doses of traditional chemotherapy cannot be given systemically because the overwhelming side effects would cause serious harm or death to the patient. Minicells offer a potential way to circumvent this important limitation and allow for far higher effective doses of chemotherapy to be delivered to tumor cells.

For recent publications on minicells :

Cell Cycle : Sept 1st, 2007 [[1]]

Cancer Cell : May 14th, 2007 [[2]]


For more general information on minicells :

New Scientist :

[[3]]

BBC :

[[4]]


Washington Post :

[[5]]

Australian Story :

[[6]] [[7]]

Side-effects

The treatment can be physically exhausting for the patient. Current chemotherapeutic techniques have a range of side effects mainly affecting the fast-dividing cells of the body. Important common side-effects include (dependent on the agent):

Immunosuppression and myelosuppression

Virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralysing the bone marrow and leading to a decrease of white blood cells, red blood cells and platelets. The latter two, when they occur, are improved with blood transfusion. Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 109/litre) can be improved with synthetic G-CSF (granulocyte-colony stimulating factor, e.g. filgrastim, lenograstim, Neupogen, Neulasta).

In very severe myelosuppression, which occurs in some regimens, almost all the bone marrow stem cells (cells which produce white and red blood cells) are destroyed, meaning allogenic or autologous bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the patient before the treatment, multiplied and then re-injected afterwards; in allogenic BMTs the source is a donor.) However, some patients still develop diseases because of this interference with bone marrow.

Nausea and vomiting

Nausea and vomiting caused by chemotherapy; stomach upset may trigger a strong urge to vomit, or forcefully eliminate what is in the stomach.

Stimulation of the vomiting center results in the coordination of responses from the diaphragm, salivary glands, cranial nerves, and gastrointestinal muscles to produce the interruption of respiration and forced expulsion of stomach contents known as retching and vomiting. The vomiting center is stimulated directly by afferent input from the vagal and splanchnic nerves, the pharynx, the cerebral cortex, cholinergic and histamine stimulation from the vestibular system, and efferent input from the chemoreceptor trigger zone (CTZ). The CTZ is in the area postrema, outside the blood-brain barrier, and is thus susceptible to stimulation by substances present in the blood or cerebral spinal fluid. The neurotransmitters dopamine and serotonin stimulate the vomiting center indirectly via stimulation of the CTZ.

The 5-HT3 inhibitors are the most effective antiemetics and constitute the single greatest advance in the management of nausea and vomiting in patients with cancer. These drugs are designed to block one or more of the signals that cause nausea and vomiting. The most sensitive signal during the first 24 hours after chemotherapy appears to be 5-HT3. Blocking the 5-HT3 signal is one approach to preventing acute emesis (vomiting), or emesis that is severe, but relatively short-lived. Approved 5-HT3 inhibitors include: Dolasetron (Anzemet®), Granisetron (Kytril®), and Ondansetron (Zofran®). The newest 5-HT3 inhibitor, palonosetron (Aloxi®), also prevents delayed nausea and vomiting, which occurs during the 2-5 days after treatment.

Another drug to control nausea in cancer patients became available in 2005. The substance P inhibitor aprepitant (marketed as Emend®) has been shown to be effective in controlling the nausea of cancer chemotherapy. The results of two large controlled trials were published in 2005, describing the efficacy of this medication in over 1,000 patients.[1]

Some studies[2] and patient groups claim that the use of cannabinoids derived from marijuana during chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat. Some synthetic derivatives of the active substance in marijuana (Tetrahydrocannabinol or THC) such as Marinol may be practical for this application. Natural marijuana, known as medical cannabis is also used and recommended by some oncologists, though its use is regulated and not everywhere legal[8] and there is still lack of sufficient studies to prove its efficacy.

Other side effects

In particularly large tumors, such as large lymphomas, some patients develop tumor lysis syndrome from the rapid breakdown of malignant cells. Although prophylaxis is available and is often initiated in patients with large tumors, this is a dangerous side-effect which can lead to death if left untreated.

A proportion of patients reports fatigue or non-specific neurocognitive problems, such as an inability to concentrate; this is sometimes called post-chemotherapy cognitive impairment, colloquially referred to as "chemo brain" by patients' groups[3]

Specific chemotherapeutic agents are associated with organ-specific toxicities, including cardiovascular disease (e.g., doxorubicin), interstitial lung disease (e.g., bleomycin) and occasionally secondary cancer (e.g. MOPP therapy for Hodgkin's disease).

See also

References

  1. ^ Gralla R, de Wit R, Herrstedt J, Carides A, Ianus J, Guoguang-Ma J, Evans J, Horgan K (2005). "Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials". Cancer. 104 (4): 864–8. PMID 15973669.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001;323:16-21. PMID 11440936.
  3. ^ Tannock IF, Ahles TA, Ganz PA, Van Dam FS. Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J Clin Oncol 2004;22:2233-9. PMID 15169812.

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Chemotherapy&oldid=161153999"